Methylsulfinylmethylthiazole

ABSTRACT

Anti-inflammatory thiazole methylalkyl sulfoxides.

United States Patent Shen et al.

[4 June 6, 1972 METHYLSULFINYLMETHYLTHIAZO LE Inventors: Tsung-YingShen, Westfield; Alexander R.

Matzuk, Colinia; Conrad P. Dorn, Jr., Plainfleld, all of NJ.

Assignee: Merck & Co., Inc., Rahway, NJ.

Filed: June 10, 1970 Appl. No.: 45,245

Related US. Application Data Division of Ser. No. 783,430, Dec. 12,1968, Pat. No. 3,551,444, which is a division of Ser. No. 592,977, Nov.9, 1966, Pat. No. 3,438,992.

U. S. Cl ..260/302 R, 260/302 S 3,288,858 11/1966 Lyness et al...260/302 S Primary Examiner-Alex Mazel Assistant Examiner-R. J.Gallagher Attorney-Martin L. Katz, Harry E. Westlake, Jr. and 1. LouisWolk [5 7] ABSTRACT Anti-inflammatory thiazole methylalkyl sulfoxides.

3 Claims, No Drawings METHYLSULFINYLMETHYLTHIAZOLE This is a division ofapplication Ser. No. 783,430, filed Dec. 12, 1968, now US. Pat. No.3,551,444, which is a division of application Ser. No. 592,977, filedNov. 9, 1966, now US. Pat. No. 3,438,992.

This invention relates to a method of treating inflammation utilizingnovel anti-inflammatory compositions containing heterocyclylmethylalkylsulfoxides. In addition, these novel compositions exhibit potentanalgesic and anti-pyretic activity and, therefore, this invention alsorelates to analgesic and antipyretic methods and compositions. Moreparticularly, this invention is concerned with the use ofheterocyclylmethyl alkyl sulfoxides as the active therapeutic ingredientin pharmaceutical compositions.

This invention also relates to certain novel sulfoxides of thestructural formula:

I I: (I)

and processes for their preparation, as well as intermediates therefor,wherein Het" represents or 6-membered heteroaromatic ring compoundshaving less than three rings. The heteroaromatic rings may contain oneor more nitrogen or sulfur atoms; or an oxygen atom together with one ormore oxygen, nitrogen or sulfur atoms. Examples of such heteroaromaticrings include thiophene, pyrrole, pyrazole, imidazole, thiazole,oxazole, isoxazole, pyridine, quinoline, pyran, isothiazole, furan,indazole, benzimidazole, benzoxazole, benzisoxazole, benzothiazole,benzodioxane and indole. The heteroaromatic nucleus may be substitutedwith one or more hydrocarbon groups or with functional substituents(shown as Y,, above, wherein n is O2). The hydro-carbon group includesparticularly the lower alkyl, such as methyl, ethyl, propyl, and butyl;and also includes an unsaturated radical such as lower alkenyl or vinyl,and a cyclic aliphatic residue (cyclic lower alkyl) such as cyclopropyl,cyclopentyl and cyclohexyl. The term functional substituent" refers to asubstituent other than hydrogen or hydrocarbons. The functionalsubstituents include halo, especially chloro, bromo or fluoro, amino,lower alkylamino, di(lower alkyl)amino, hydroxy, lower alkoxy, mercapto,lower alkylmercapto and nitro.

The carbon atom a to the heterocyclic moiety may contain hydrogen or besubstituted with a lower alkyl or lower alkenyl group (R and R R may belower alkyl or lower alkenyl. it is preferred that R and R be hydrogenand R, lower alkyl.

The heterocyclymethyl methyl sulfoxides of this invention represent anew milestone in the continuing search for potent, low toxicity,anti-inflammatory agents. These sulfoxides provide a uniquestructure-activity relationship which not only has resulted in highanti-inflammatory, anti-pyretic, and analgesic potency, but also appearto exhibit a biological profile quite different from the salicylates andphenylbutazone. The above defined sulfoxide compounds are administratedto a patient in a dosage unit form, a pharmaceutically acceptablecomposition containing a therapeutically effective amount of aheterocyclylmethyl methyl sulfoxide such as4-methylsulfinylmethylthiazole.

A preferred embodiment of this invention is a method of treating adisease which is symptomatically characterized by pain, fever and/orinflammation which comprises the administration to a patient in dosageunit form of between about 0.01 and 5 gm. of the heterocyclylmethylaliphatic sulfoxide per day. On a kilogram basis, it is preferred toutilize between about 0.5 mg./kg. and 70 mg.-/kg. per day of theheterocyclylmethyl aliphatic sulfoxide of this invention.

Another embodiment of this invention is the provision of pharmaceuticalcompositions in dosage unit form which comprise from about 5 to 500 mg.,and preferably from 25 to 250 mg., of the heterocyclylmethyl aliphaticsulfoxide of the above formula. 4-Methylsulfinylmethylthiazole, in oraldosage form, comprising about 25 to about 500 mg. is a preferredpharmaceutical composition of this invention.

in a preferred embodiment of this invention, the novelheterocyclylmethyl aliphatic sulfoxides (I) wherein R and R are eachhydrogen, are prepared by reacting a compound having formula (II) withan alkali metal R -mercaptide (III), to form a heterocyclylmethylthiocompound (lV), which is then oxidized to form compound (I); asillustrated by the following reaction scheme: (1)

(Y)nHetCH2 4 (II) (III) wherein X represents chloro, bromo or iodo and Mrepresents an alkali metal atom.

The above reaction takes place'by adding a heterocyclic halomethylcompound (I1) to an alcoholic solution of an alkali metal R -mercaptide(Ill), prepared by adding an R,-mercaptan to an alcoholic solution of analkali metal hydroxide, to form compound (lV) (process step i) andoxidizing compound (IV) to the desired heterocyclylmethyl R -sulfoxide l(process step 2). When an acid salt of compound (ll) is used, it ispreferred that an alkaline agent, such as potassium hydroxide be addedfirst to the solution of compound (ll) before adding compound (II) tothe basic mercaptide solution (11]).

It is preferred that the reaction mixture in step 1) be basic. Generallythe reaction mixture is basic because the R,-mercaptide reactant impartsbasicity to the mixture. However, the point at which the reactionmixture is made basic is not critical and therefore if it is desired,compound II and compound lll may be mixed in an inert solvent to whichis then added a strong base. It is preferred to reflux the mixtureovernight; however, reaction temperature and time are not critical andtherefore, any suitable time and temperature may be used. The solventused for this reaction is preferably ethanol, however any inert solventwhich is capable of dissolving the reactant may be used. The ratio ofreactants may be varied, however it is preferred to carry out thereaction using an excess of R,-mercaptide. The oxidation step 2 may becarried out employing any number of oxidizing agents. Such agents aschromic acid, permanganate, peroxide and alkali metal metaperiodate areamong those which can be used. It is preferred, however to use sodiummetaperiodate as the oxidizing agent. In the selection of an oxidizingagent, the probability of destroying the heterocyclic function to anyextent should be considered. Therefore, it is preferred to use oxidizingagents such as metaperiodate which are incapable of destroying theheterocyclic moiety. It is preferred to use a ratio of 1:1 of oxidizingagent to compound (IV). Using less oxidizing agent will reduce the yieldand the use of excess oxidizing agent will further oxidize the sulfoxidecompound (I) to the corresponding sulfone.

Generally, the chloro derivative of heterocyclic reactant (ll) (x=cl) ispreferred because of its greater availability. If the chloro-derivativeis insufficiently reactive for practical purposes, the chloro group inreactant (ll) may be replaced by iodo, for example, by heating with analkali metal iodide.

(Y),,HetCH -Cl -(Y),,-HetCH I In the alternative, the reaction of a(Y),,-HetCl-l Cl compound (II) with the alkali metal R -mercaptide (Ill)may be carried out in the presence of a small amount of an alkali metaliodide as a catalyst. The heteroaromatic ring compounds (II) where X ishalogen are known in some instances. They can also be prepared by knowntechniques.

In a preferred embodiment of this invention, the -CH Cl group isintroduced into the heterocyclic ring by reaction with formaldehyde anddry l-lCl, in the presence of a condensing agent such as zinc chloride.1n the alternative this reaction can be carried out in two steps byreacting the heterocyclic compound with an aqueous solution offormaldehyde and aqueous HCl to give the hydroxymethyl substituent,which may be converted into the derivative by r reaction with thionylchloride.

The hydroxymethyl derivative may be prepared also from a heterocycliccompound already having a forrnyl substituent (--CHO) by reduction, forexample, with sodium borohydride; or from a heterocyclic compound havinga carbonylethoxy substituent (COOC l-l by reduction, for exampie, withlithium aluminum hydride. The carbonylethoxy substituent (COOC H may bederived from a corresponding carboxy substituent (COOl-l) byesterification. The carboxy substituent in turn may be obtained byoxidation of a methyl substituent, all by methods known in the art.Thus, a

halomethyl substituent of the heterocyclic reactant (II) may beintroduced into the heterocyclic ring directly, or derived from a knownheterocyclic compound which has a methyl, carboxy, carbonylalkoxy,formyl or hydroxymethyl group already present in the ring.

lndole compounds having the following formula:

VLI

Jr (W) wherein R and R represents those substituents previouslymentioned for the heteroaromatic moiety can be prepared in two steps byreacting an indole compound having formula v:

Clln M N H (V) Ii (VI) with an aqueous solution of dimethylamine and anaqueous solution of formaldehyde to obtain a compound having formula(Vi), wherein R and R have the meaning above defined, which compound isthen reacted with an alkali metal R,-mercaptide (ill) in the presence ofdimethyl sulfate. The compounds of formula (V) can be readily preparedfollowing the procedures set forth in columns 2 and 3 of U.S. Pat. No.2.825.734. The novel heterocyclic sulfoxide compounds wherein R and/or Rare other than hydrogen are prepared by one of two process steps,depending upon the type of heterocyclic moiety involved. The followingprocess may be illustrated by the following reaction schemes:

A. Where the heterocyclic moiety contains a nitrogen atom.

wherein R is an alkyl or alkenyl, R is hydrogen, alkyl or alkenyl and Rand Y are as previously defined. Compound VI is reacted withN-halosuccinimide in an inert solvent such as carbon tetrachloride,preferably in the presence of a catalytic amount of peroxide, at or nearambient temperatures, to form compound Vll. Compound Vll is then reactedin accordance with step l as shown previously for compound 11, and theproduct VIII is further reacted in accordance with step 2 as shownpreviously for compound IV.

B. Where the heterocyclic moiety contains oxygen and/or sulfur atoms.Using a sulfur derivative as an example, the following reaction schemeis followed:

R, and R. being hydrogen, alkyl or alkenyl or alkenyl; only one of R,and R being hydrogen at the same time. The thiophene compound X isreacted with an alkyl or alkenyl iodide in the presence of a strong baseto obtain compound X]. If it is desired that R and R each be other thanhydrogen. two equivalents of base and iodide are used. if one of R, orR. is to be hydrogen, then one equivalent of base and iodide is used perequivalent ofthe thiophene compound.

Procedure A may also be used to prepare the (1 substituents for all ofthe heterocyclic compounds. Therefore, it can be seen that bothprocedures A and B are applicable to the sulfur and oxygenheterocyclics.

Included within the scope of this invention are compounds wherein thesulfoxide moiety is attached to the nitrogen of the heterocyclicradical. These compounds are prepared by the following reaction scheme:

wherein R R R,,, Y and n are as previously defined.

in this reaction scheme, the starting heterocyclic compound is reactedwith sodium hydride to activate the nitrogen. This activated compound issubsequently reacted with a chlorosulfide compound to form aheterocyclic sulfide compound, which compound is then oxidized to thedesired sulfoxide compound.

EXAMPLE 1 2-Chloromethyl-5-chlorothiophene A mixture of concentrated HCl(45.6 ml.) and 37 percent formalin (45 ml.) is saturated with dry HCl atOl0 C. with stirring, and added in a slow stream to a mixture of 5-chlorothiophene (71.6 grams) and zinc chloride at 3540 C. lgram). Thereaction mixture is then stirred for an additional 2 hours. Cold water(114 ml.) is then added. The oil which separates is washed two timeswith cold water. Dicyclohexylamine (2 cc.) is then added and the productdistilled under vacuum; the portion boiling at -96 C/9-10 mm. iscollected.

EXAMPLE 2 2-Chloromethylthiazole Step A: Preparation ofZ-hydroxymethylthiazole Thiazole (17 grams, 14.2 mole) and 40 percentaqueous formalin solution (50 ml.) are heated at about 120 C. for eighthours with agitation. The product is cooled and then acidified with 2.5NHCl and extracted with ether. The aqueous solution is neutralized withsolid potassium carbonate with stirring. The product is then extractedfour times with ether. The combined ether extracts are dried over sodiumsulfate, filtered and concentrated. The yellow liquid remaining is takenup in ml. ofa mixture of 1:1 H ozconc. HCl. The solution is thenfiltered and concentrated to give an oil which solidifies. The productis triturated with ethanol, filtered and washed with ethanol to yield1.76 grams of 2-hydroxymethylthiazole hydrochloride, m.p. l23-l 255 C.

Step B: Preparation of 2-chloromethylthiazole EXAMPLE 34-Chloromethylthiazole Step A: Preparation of 4-hyroxymethylthiazole4-Formylthiazole (20 grams, 0.177 mole) and ethanol (175 ml.) is addedto sodium borohydride (3.4 g., 0.089 m.) in 75 ml. of ethanol. Themixture is stirred and kept at about 25 2 C. with an ice bath. Theaddition takes approximately 0.5 hour, and stirring is continued for anadditional 1.0 hours at room temperature. Glacial acetic acid (6 ml.) inwater (20 ml.) is added dropwise. The product is evaporated under vacuumto a small volume and extracted three times with chloroform. Thechloroform solution is washed with saturated sodium bicarbonate and thenwater. It is then dried and evaporated under vacuum to give 3.44 gramsof 4-hydroxymethylthiazole.

Step B: Preparation of 4-chloromethylthiazole Thionyl chloride 10 ml.)is added dropwise with cooling to the 4-hydroxymethylthiazole (3.44grams) of Step A. A vigorous reaction results. After completion, theexcess thionyl chloride is then removed under vacuum to yield 4-chloromethylthiazole hydrochloride.

EXAMPLE 4 3-Chloromethylpyrazole Step A: Preparation of 3-carboxypyrazole 3-Methylpyrazole (45 grams) is dissolved in 2,700 ml.of water. Powdered potassium permanganate (180 grams) is added inportions starting at room temperature and gradually heating to about 90C. on a steam bath. After the purple color is gone the product isfiltered and the solid washed with water. The filtrate is evaporatedunder vacuum to a small volume and then acidified with concentrated HClto pH-2 and cooled. The precipitate is filtered and washed with coldwater and air-dried to give 25.2 grams. The filtrate is evaporated todryness, extracted with ethanol and evaporated to dryness again. Theresidue is extracted again with boiling ethanol and taken to dryness togive 23.6 grams. The combined residues equal 48.8 grams.

Step B: 3-Ethoxycarbonylpyrazole Ethanol (300 ml.) is added to the3-carboxy-pyrazole (48.8 grams) of Step A. The mixture is saturated withHCl and then refluxed with stirring for about 5 hours. HCl isoccasionally passed in. The product is evaporated under vacuum and thesolid residue distributed between sodium carbonate solution andchloroform. The chloroform layer is dried and evaporated under vacuum.The residue is recrystallized from boiling methanol to give 36.2 gramsof 3-ethoxycarbony1pyrazole.

Step C: 3-Hydroxymethylpyrazole Lithium aluminum hydride (16.3 g.) in1.5 liters of dry ether is refluxed with stirring overnight with3-ethoxycarbonylpyrazole (30.3 grams). Water (about 55 milliliters) isadded dropwise and the ether is evaporated under vacuum. The

residue is treated with methanol and saturated with carbon dioxide. Theproduct is heated to boiling and filtered. The solid is washed withboiling methanol and the methanol solution evaporated under vacuum tosmall volume. The product is then heated to boiling and filtered.Evaporation of the solvent yields 21.00 grams of a syrup which is the3-hydroxymethylpyrazole.

Step D: Preparation of 3-chloromethylpyrazole Thionyl chloride (35 ml.)is added dropwise to the 3- hydroxymethylpyrazole (21.0 g.) obtained inStep C. The reaction mixture is then warmed on a steam bath for 15minutes. The excess thionyl chloride is removed under vacuum and theresidue washed with ether and dried under vacuum to yield 31.1 g. of3-chloromethylpyrazole hydrochloride.

EXAMPLE 5 4-Chloromethylimidazole Step A: Preparation of4,5-dicarboxyimidazole 4,5-Di(ethoxycarbonyl)imidazole (100 grams) in400 ml. in 2.5N sodium hydroxide solution (400 ml.) is allowed to standat room temperature overnight. The disodium salt precipitates. It ismixed with concentrated l-lCl, cooled and filtered. The filtrate isstirred with fresh water, filtered and airdried to give 72 grams of4,5-dicarboxyimidazole.

Step B: Preparation of 4-anilinocarbonylimidazole A mixture of4,5-dicarboxyimidazole from Step A (200 grams) and aniline 1000 ml.) isrefluxed with stirring for three days. The aniline is then removed bysteam distillation. The product is filtered, washed with water and thendissolved in acid. The insolubles are filtered off and the filtrate madealkaline with sodium carbonate. The precipitate is then filtered andwashed with water.

Step C: Preparation of 4-carboxyimidazole The 4-anilinocarboxyimidazolefrom Step B is added to 1000 ml. of concentrated HCl and the mixturerefluxed for 4 hours and then taken to dryness. The residue is dissolvedin water, made alkaline with sodium carbonate, extracted with ether,charcoaled, adjusted to pH=4 with HCl, and allowed to stand in the coldovernight. The product is then filtered and washed with cold water. Thefiltrate is evaporated at room temperature and atmospheric pressure. Theresidue is washed with cold water and air-dried to yield grams.

Step Di Preparation of 4-ethoxycarbonylimidazole A mixture of the4-carboxyimidazole from Step C and 1 /2 liters of ethanol is saturatedwith HCl and refluxed until homogeneous. The reaction mixture isevaporated under vacuum. The residue is then dissolved in water,charcoaled, and treated with sodium bicarbonate. The solid is filtered,washed with cold water, and air-dried. The aqueous filtrate is extractedwith chloroform, and the chloroform evaporated under vacuum. The totalyield of product is 73 grams.

Step E: Preparation of 4-hydroxymethylimidazole4-Ethoxycarbonylimidazole (28 grams) from Step D is added portionwisewith stirring over a half hour period to lithium aluminum hydride (10g.) in 30 ml. of ether. After the addition is complete, the reactionmixture is allowed to stand overnight. Water (25 m1.) is added dropwise.The resulting solid is filtered and suspended in 300 ml. of hotmethanol, saturated with carbon dioxide, and filtered. The product isextracted again with hot methanol. The extracts are combined andevaporated under vacuum. The residue is taken up in 300 ml. of hotethanol, filtered and evaporated under vacuum. The residue is thentreated with ethanolic HCl. The resulting solid is cooled, diluted withether, and then filtered. The product is then washed with ether anddried under vacuum.

Step F: Preparation of 4-chloromethylimidazole4-l-lydroxymethylimidazole hydrochloride (10 grams) from Step E issuspended in 50 ml. of dry benzene, and 14 ml. of thionyl chloride in 50ml. of benzene is added slowly with stirring. After addition iscomplete, the reaction mixture is refluxed with stirring for 2 hours. Itis then evaporated under vacuum, to yield the 4-chloromethylimidazolehydrochloride.

EXAMPLE 6 2-Iodomethyll ,4-benzodioxane A mixture of2-chloromethyl-1,4-benzodioxane (12 g.) in acetone (50 ml.) and sodiumiodide (9.75 g.) is stirred and refluxed for 3 days. The precipitatewhich forms is filtered off and washed with acetone. The filtrate isevaporated under vacuum and extracted with chloroform, to yield 14.81grams ofan oil n 1.5780.

EXAMPLE 7 2-Methyl-3-methylthiomethyl-S-methoxyindole Step A:Preparation of 2-methy1-3-dimethylaminomethyl-5- methoxyindole2-Methyl-6-methoxyindole (8.0 grams) is dissolved in 35 ml. of glacialacetic acid with warming. To this solution is added 25 percent aqueousdimethylamine (9.0 g.) and 37 percent formalin solution (4.1 g.). Aprecipitate forms and the mixture is stirred at room temperatureovernight. It is then diluted with water and methanol and evaporatedunder vacuum. The residue is extracted with water and made alkaline withammonium hydroxide. The precipitate which forms is filtered off, washedwith water, and air-dried to give2-methyl-3-dimethylaminomethyl6-meth0xy-ind0le, m.p. l42-l47 C. Theproduct is dissolved in dilute HCl, extracted two times with ether,filtered, and made alkaline with 2.5N sodium hydroxide. lt is thencooled, filtered, washed with water, and air-dried. The product ispurified by recrystallization from aqueous acetone solution to yield aproduct, m.p. 245249 C.

C, 71.52; H, 8.31 C, 71.36; H, 8.32

Analysis Calcd. for C H N O:

Found:

Step B: Preparation of 2methyl-3-methylthiomethyl-5- methoxyindoleEXAMPLE 8 l-Methylthiomethylimidazole To a suspension of 0.1 moles ofsodium hydride in 50 cc. of dry dimethylformimide, which is stirredunder nitrogen and maintained at 5 C., is added a solution of 0.1 molesof imidazole in 50 cc. of dry dimethylformamide. The reaction mixture isstirred for 30 minutes after the evolution of hydrogen ceases. Thenthere is added a solution of O. 12 moles of chloromethylmethylsulfide in50 cc. of dry dimethylformamide and the reaction mixture is stirredovernight at room temperature. The reaction mixture is concentrated invacuo, extracted well with boiling chloroform and the combinedchloroform extracts are chromatographed on silica gel. Elution withmethanol (0-5 percent). in methylene chloride gives1-methylthiomethylimidazole.

When the 2-substituted imidazoles are used in place of imidazole in theprocedure of Example 8, the following corresponding2-substituted-l-methylthiomethyl-imidazoles are obtained:

1-methylthiomethyl-Z-methylimidazole 1-methylthiomethyl-2-ethylimidazolel-methylthiomethyl-2-butylimidazole l-methylthiomethyl-2-bromoimidazolel-methylthiomethyl-2-nitroimidazolel-methylthiomethyl-2-methylthioimidazole.

Similarly, when the 4(5)-substituted imidazoles are used in place ofimidazole in the procedure of Example 8, the following corresponding4-substituted and 5-substituted-lmethylthiomethylimidazoles areobtained:

1-methylthiomethyl-4-methylimidazolel-methylthiomethyl-S-methylimidazole l-methylthiomethyl-4-ethylimidazole1-methylthiomethyl-5-ethylimidazole l-methylthiomethyl-4-propylimidazolel-methylthiomethyl-5-propylimidazole l-methylthiomethyl4-butylimidazole1methylthiomethyl-S-t-butylimidazole 1-methylthiomethyl-4-nitroimidazolel-methylthiomethyl-S-nitroimidazole 1-methylthiomethyl-4-bromoimidazole1-methylthiomethyl-S-bromoimidazole1-methylthiomethyl-4-methoxyimidazole1-methylthiomethyl-S-methoxyimidazole.

Similarly, when benzimidazole is used in place of imidazole in Example8, there is obtained methylthiomethylbenzimidazole.

When the 3(5)-substitutecl pyrazoles are used in place of imidazole inExample 8, the following corresponding 3(5)-substituted-1-methy1thiomethylpyrazoles are obtained:

1-methylthiomethyl-3(5)-methylpyrazolel-methylthiomethyl-3(5)-ethylpyrazole1-methylthiomethyl-3(5)-propylpyrazolel-methylthiomethyl-3(5)-butylpyrazolel-methylthiomethyl-3(5)-bromopyrazole.

When the 4-substituted pyrazoles are used in place of imidazole inExample 8, the following corresponding4-substituted-1-methylthiomethylpyrazoles are obtained:

l-methylthiomethyl-4methylpyrazole 1-methylthiomethyl-4-ethylpyrazolel-methylthiomethyl-4-propy1pyrazole l-methylthiomethyl-4-bromopyrazole1-methylthiomethyl-4-chloropyrazole l-methylthiomethyl-4-nitropyrazolel-methylthiomethyl-4-ethoxypyrazole.

EXAMPLE 9 2-Methylthiomethylthiazole 0.1 Moles ofmethylthiothioacetamide and 0.1 moles of chloroacetaldehyde are refluxedfor 3 hours under nitrogen. The reaction mixture is poured into icewater, neutralized with sodium bicarbonate and extracted well withether. The combined ether extracts are dried over sodium sulfate andconcentrated to yield crude 2-methylthiomethylthiazole.

When l-chloro-2-propanone, l-chloro-2-butanone, lchloro-2-pentanone andl-chloro-2-hexanone are used in place of chloroacetaldehyde in the aboveexample, there are obtained the corresponding4-substituted-Z-methylthiomethylthiazoles.

EXAMPLE 1O 4-I-Iydroxy-2-methylthiomethylthiazole A mixture of 0.1 molesof methylthiothioacetamide and 0.15 moles of chloroacetic acid arerefluxed for 3 hours in 250 cc. of toluene under nitrogen. The reactionmixture is filtered while hot and then concentrated to yield crude4-hydroxy-2- methylthiomethylthiazole.

EXAMPLE I l 4-methoxy-2-methylthiomethylthiazole To a stirred suspensionof 0.05 moles of sodium hydride in 50 cc. of dry dimethylformamide at -5is addeddropwise 0.05 moles of 4-hydroxy-2-methylthiomethylthiazole in50 cc. dry dimethylformamide. After the evolution of hydrogen hasceased, there is added dropwise 0.05 moles of methyl iodide. Thereaction mixture is stirred at room temperature overnight, concentratedand extracted between ether and water. The aqueous layer'is separated,extracted well with ether and the combined ether extracts dried oversodium sulfate and concentrated to yield crude 4-methoxy-2-methylthiomethylthiazole. Chromatography on 500 gm. of silica gel andelution with methanol in methylene chloride (0-5 percent) gives pure4-methoxy-2-methylthiomethylthiazole.

EXAMPLE l2 5Chloro-2-methylsulfinylmethylthiophene A.5-Chloro-2-methylthiomethylthiophene A solution of 0.1 moles of sodiumhydroxide in 200 cc. of ethanol is saturated with methyl mercaptan.There is then added with stirring a solution of 0.1 moles of2-chloromethyl- 5-chlorothiophene in 50 cc. of ethanol. The reactionmixture is refluxed overnight, cooled and 500 cc. of ether added. Themixture is filtered and concentrated to give crude 2- methylthiomethyl-S-chlorothiophene.

5-ChIoro-2-methylsulfinylmethylthiophene To 210 ml. of a 0.5M solutionof sodium metaperiodate at 0 is added 0. 1 moles of 5-chloro-2-methylthiomethylthiophene. The reaction mixture is stirred overnight at0-5 C. The precipitated NaIO is removed by filtration and the filtrateextracted well with chloroform. The

combined chloroform extracts are dried over sodium sulfate andconcentrated in vacuo. The residue is chromatographed on 500 grams ofsilica gel. Elution with methanol-methylene chloride (O-IO percent)gives 5-chloro-2-methylsulfinylmethylthiophene.

Similarly, when 4-chloromethylpyridine, 2-chloromethylpyridine,3-chloromethylpyridine, 2-chloromethylthiazole, 4- chloromethylthiazole,3-chloromethylpyrazole, 4- chloromethylimidazole,2-chloromethylbenzimidazole or 2- iodomethyl-1,4-benzodioxane obtainedfrom Examples [-7 are used in place of 2-chloromethyl-5-chlorothiophenein the above example, there is obtained the corresponding heterocyclicsulfinyl compound.

Simlilarly, when the l-methylthiomethyl heterocyclic compounds obtainedfrom Example 8 are used in place of 5-chloro-2-methylthiomethylthiophene in part B of the above example, thereare obtained the corresponding l-methylsulfinylmethyl heterocycliccompounds.

Similarly, when the 2-methylthiomethylthiazole, the4-substituted--2-methylthiomethylthiazoles obtained from Example 9,4-hydroxy-Z-methylthiomethylthiazole obtained from Example IO, and4-methoxy-2-methylthiomethylthiazole obtained from Example II are usedin place of 5-chloro-2- methylthiomethylthiophene in part B of the aboveexample, there are obtained the corresponding2-methylsulfinylmethylthiazole compounds.

Similarly, when 2-methyl-3-methylthiomethyl-5-methoxyindole obtainedfrom Example 7 is used in place of 5-chloro-2- methylthiomethylthiophenein part B of the above example, there is obtained2-methyl-3-methylsulfinyl-methyl-5-methoxyindole.

WHAT IS CLAIMED IS:

1. A compound of the formula wherein Y is halo, loweralkyl having I to 4carbon atoms, loweralkenyl having 2 to 4 carbon atoms, hydroxy,lower-alkoxy having one to four carbon atoms, mercapto,loweralkylmercapto or nitro, n is l to 2 and R is loweralkyl having oneto four carbon atoms.

2. 4-I-Iydroxy-2-methylsulfinylmethy]thiazole.

3. 4-methoxy-2-methylsulfinylmethylthiazole.

2. 4-Hydroxy-2-methylsulfinylmethylthiazole. 3.4-methoxy-2-methylsulfinylmethylthiazole.